Trastuzumab uptake in HER2-positive breast cancer patients: a systematic review and meta-analysis of observational studies

Accepted Manuscript Title: Trastuzumab uptake in HER2-positive breast cancer patients: a systematic review and meta-analysis of observational studies Authors: Antony P. Martin, Jennifer Downing, Madeleine Cochrane, Brendan Collins, Ben Francis, Alan Haycox, Ana Alfirevic, Munir Pirmohamed PII: DOI: Reference:

S1040-8428(18)30095-7 https://doi.org/10.1016/j.critrevonc.2018.07.012 ONCH 2598

To appear in:

Critical Reviews in Oncology/Hematology

Received date: Revised date: Accepted date:

23-2-2018 18-7-2018 31-7-2018

Please cite this article as: Martin AP, Downing J, Cochrane M, Collins B, Francis B, Haycox A, Alfirevic A, Pirmohamed M, Trastuzumab uptake in HER2-positive breast cancer patients: a systematic review and meta-analysis of observational studies, Critical Reviews in Oncology / Hematology (2018), https://doi.org/10.1016/j.critrevonc.2018.07.012 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Trastuzumab uptake in HER2-positive breast cancer patients: a systematic review and metaanalysis of observational studies Authors: Antony P. Martin1,2* Jennifer Downing1,2 Madeleine Cochrane3 Brendan Collins4 Ben Francis5 Alan Haycox6 Ana Alfirevic1,2 Munir Pirmohamed1,2 Institutions: (1) National Institute for Health Research, Collaborations for Leadership in Applied Health Research and Care, North West Coast (NIHR CLAHRC NWC), (2) Wolfson Centre for Personalised Medicine, University of Liverpool (3) Research Institute for Sport and Exercise Sciences

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(RISES), Liverpool John Moores University (4) Department of Public Health & Policy, University of Liverpool, (5) Department of Biostatistics, University of Liverpool, (6) Liverpool Health Economics,

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University of Liverpool Management School

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Antony P. Martin Wolfson Centre for Personalised Medicine Department of Molecular & Clinical Pharmacology University of Liverpool, Block A: Waterhouse Buildings, 1–5 Brownlow Street, Liverpool, L69 3GL 0151 795 3612 [email protected]

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Correspondence:

Individual Author Contributions: APM, JD, MC, BC, BF, AH, AA and MP were involved with the

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conception and design of the study. APM and MC were involved with acquisition of data. APM, BC and BF were responsible for analysis and interpretation of data. All authors contributed to drafting the

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article, revising it critically for important intellectual content and had final approval of the version to

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be published.

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Word Count: 5312 excluding title page, abstract, references, tables, and figure legends. (Abstract 315 Words)

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Running Head: Disparities in targeted trastuzumab therapy

Abstract Overexpression of the HER2 gene is predictive of treatment benefit with trastuzumab therapy for breast cancer (BC) patients. The study objective was to investigate whether all eligible patients with HER2positive BC initiated trastuzumab therapy. A systematic search was conducted through PubMed, Web of Science PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Cochrane Library. From 2651 studies identified, 107 observational studies were included for full text review, of which 26 met the inclusion criteria and an additional 7 studies were identified through citation

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searching. Two independent reviewers extracted data for accuracy and completeness. From 33 observational studies, 14,644 patients were exposed to trastuzumab therapy. Age range varied

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across studies; the youngest cohort had a median age of 50 and the oldest had a median age of 84. Sample sizes ranged from 11 to 1928 and included patients from 10 countries. Studies were

heterogenous and few studies accounted for confounders. We identified large variability in uptake of trastuzumab in HER2-positive early BC patients (9.1-100%) and metastatic BC patients (50.8-84.0%).

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The pooled uptake was 71.3% (95% CI 64.6-77.9%), with high heterogeneity (I2=99.05%). The most conservative predictors of higher uptake included younger age (OR 2.09; 95% CI 1.36-3.20) and lower

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Charlson Comorbidity Index of patients (OR 1.62; 95% CI 1.32-1.99). In addition, tumour

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characteristics including higher tumor grade (OR 1.73; 95% CI 1.23-2.45), larger tumor size (OR 1.80; 95% CI 1.54-2.10), advanced tumor stage (OR 2.07; 95% CI 1.44-2.96) and hormone receptor negative

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tumor (OR 1.54; 95% CI 1.35-1.77) were associated with higher uptake.

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The uptake of trastuzumab therapy varied widely between studies and across subgroups suggesting that there may be some inequalities in the use of this agent. However, our findings should be interpreted with caution due to study heterogeneity and potential confounding, and thus additional studies of

in uptake.

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individual level data which control for confounders are needed to understand more about inequalities

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Registration: Systematic review protocol was registered with PROSPERO, identification number: CRD42017073218

Funding Source: This study was funded by the National Institute of Health Research Collaboration for

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Leadership in Applied Health Research and Care North West Coast (NIHR CLAHRC NWC).

Keywords: HER2-positive; breast cancer; trastuzumab; uptake; disparity

1. Introduction Trastuzumab (Herceptin) is a monoclonal antibody which targets the extracellular domain of the HER2 receptor and acts by different mechanisms to inhibit cell growth by prevention of HER2 dimerization, downregulation of the HER2 receptor by endocytic destruction of the receptor, accumulation of the cyclin-dependent kinase (CDK) inhibitor p27 and cell cycle arrest, induction of antibody-dependent cellular cytotoxicity, and inhibition of constitutive HER2 cleavage/shedding mediated by metalloproteases.1 Over-expression of the human epidermal growth factor receptor 2 (HER2) is seen in

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approximately 15-30% of breast cancers in women and is of both prognostic value and predictive of treatment benefit.2,3 Indeed, trastuzumab therapy has revolutionized the treatment of HER2-positive

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disease in both adjuvant2,4–7 and metastatic settings.3

Since approval for use by the European Medicines Agency (EMA) and US Food and Drug Administration (FDA), trastuzumab targeted therapy has been rapidly adopted for use.8 The American Society for Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO)

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recommend testing every primary invasive breast cancer to guide HER2-targeted therapy.9,10 Trastuzumab therapy is widely considered a highly effective treatment with a favorable benefit/risk

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profile with gains in overall survival.11,12 Despite concern of a relatively high acquisition cost,

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trastuzumab therapy in HER2 positive breast cancer patients was widely found to be a cost-effective oncology therapy across payers within developed countries.11–13 However, little is known about

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inequalities in the implementation of targeted trastuzumab therapy in clinical practice.8

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By 2030, the global rate of women diagnosed with breast cancer is predicted to increase to 3.2 million per year. The economic cost of cancer is estimated to be up to 4% of global GDP and improvements in both treatments and reductions in health disparities provide an opportunity to deliver significant

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economic benefits.14 Since 2012, the recorded incidence of breast cancer in the USA has converged between black and white women,15 but substantial racial disparities have previously been identified in

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the stage of diagnosis, treatment patterns and mortality rate.16,17 The objective of this systematic review was to investigate whether all eligible patients with HER2-positive breast cancer initiated trastuzumab therapy.

2. Methods

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The systematic review protocol was registered with PROSPERO, the international database of prospectively registered systematic reviews (identification number CRD42017073218), conducted according to the Centre for Reviews and Dissemination’s guidance for undertaking reviews in healthcare 18 and reported according to the Preferred Reporting Items for Systematic Reviews and MetaAnalysis with a focus on health equity (PRISMA-E) guidelines.19

2.1

Data Sources and Searches

A systematic search of PubMed, Web of Science, PsychINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL), The Cochrane Library and Cochrane Central Register of Controlled Trials (CENTRAL) and Cochrane Methods search was conducted to July 2017. The search terms consisted of two clauses combined with the Boolean ‘AND’ operator. Filters were applied to restrict studies to human subjects and English-language. Further articles were identified from searching reference lists of included studies and forward citation searching using Google Scholar. In addition, grey literature was

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Peters et al. (2015)

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Palmieri et al. (2011)

Munck et al. (2011)

Liebrich et al. (2007)

Li et al. (2017)

Kaufman et al. (2012)

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Herk-sukel et al. (2013)

Haas et al. (2011)

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Noonan et al. (2012)

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Neugut et al. (2014)

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Goddard et al. (2012)

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Freedman et al. (2013)

Cyr et al. (2011)

Coulson et al. (2010)

Chavarri-Guerra et al. (2014)

Chan and McGregor (2012)

Boons et al. (2016)

Byfield et al. (2016)

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Clinical factors Tumour stage Tumour grade Tumour size Lymph nodes (positive/number) Hormone receptor status (ER/PR) Comorbidity (CCI) Menopause Year of diagnosis Caseload of surgeon Mastectomy vs. breast conserving Mastectomy vs. mastectomy and radiation Mastectomy vs. mastectomy and radiation Mastectomy vs. lumptectomy Adjuvant endocrine/hormonal therapy Chemotherapy anthracycline- vs. non-anthracyclinebased Adjuvant radiotherapy Adjuvant chemotherapy Neoadjuvant chemotherapy Psychosocial factors Patient refused therapy Clinician withheld therapy and no reason given/not indicated Sociodemographic factors Education Socioeconomic status Income

Barron et al. (2009)

Adusumilli et al. (2017)

The full search strategy is detailed in Error! Reference source not found. in

Marla et al. (2010)

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searched by applying a combination of the search terms from the original search using Google Scholar.

Employment Insurance status Marital status Age Ethnicity Geographical region (urban/rural, SEER region) Institution

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Notes: ~, tested, but not statistically significant; ✓, tested in univariable analyses, and significant; ✓✓, tested multivariable, and significant.

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Table 3 Summary of meta-analysis of factors associated with initiation of trastuzumab therapy Total events (ref)

Heterogeneity

1834/2328 652/796

747/1283 1929/2815

P=0.0002, I2=76% P=0.03, I2=54%

3.55 (2.415.23)**** 2.07 (1.442.96)***

1920/3274 1874/2754

184/425 1018/1873

P=0.008, I2=63% P=<0.00001, I2=81%

2.55 (1.534.25)** 1.74 (1.232.47)*

559/940 1297/1844 794/1133

108/341 1096/2018 2500/2601

P=0.41, I2=0% P=0.79, I2=0% P=0.88, I2=0%

3.16 (2.434.11)**** 2.02 (1.762.32)**** 1.80 (1.542.10)****

38–40,42,43,46,47

1072/1514

1218/2221

P<0.00001, I2=90%

1.63 (0.952.80)

25,30,38,40,42,43,46–48

1227/1733 213/374 103/147

2068/3345 231/337 71/95

P=0.74, I2=0% P=0.32, I2=14% P=0.99, I2=0%

1.54 (1.351.77)**** 1.05 (0.741.50) 0.79 (0.441.42)

1802/2611 2094/3205

595/1127 193/407

P=0.22, I2=29% P=0.55, I2=0%

1.62 (1.321.99)**** 1.52 (1.221.88)***

1558/1926 2710/3398 3409/4235

2413/3525 978/1534 485/1034

P=0.002, I2=68% P=0.002, I2=72% P<0.00001, I2=81%

2.15 (1.582.92)**** 2.59 (1.883.56)**** 3.90 (2.536.03)****

2870/4205 2200/3412 2870/4205

296/440 421/575 717/1015

P=0.15, I2=38% P=0.57, I2=0% P=0.11, I2=44%

1.26 (0.921.72) 0.82 (0.661.01) 0.99 (0.791.24)

24,25,30,33,38,46–48

Tumour grade: ≥Grade 2 vs. grade 1 (ref) ≥Grade 3 vs. ≤grade 2 (ref)

38–40,42,43,46–48

Tumour size: ≥1cm vs. <1cm (ref) ≥2cm vs. <2cm (ref) ≥3cm vs. <3cm (ref)

24,25,30,33,38,46–48

30,38,40,43,46–48,58

48,54 39,40,42–44,46,47 40,42–44,46,47

Comorbidity (CCI): CCI 0 vs. >0 (ref) CCI ≤1 vs. >1 (ref)

24,25,33,39,40

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Hormone receptor status: HR positive vs. negative (ref) ER positive vs. negative (ref) PR positive vs. negative (ref)

25,40

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Lymph node status: Positive vs. negative

30,33,38,40,41,43,46,54

Age: <50 vs. ≥50 (ref) <60 vs. ≥60 (ref) <70 vs. ≥70 (ref)

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30,33,38,42,43,47 30,33,42,43,47

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30,38,40,41,43,46,54

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30,38,41,47,51,54

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Ethnicity: White vs. black (ref) White vs. other (ref) White vs. non-white (ref)

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Tumour stage: ≥Stage II vs. stage I (ref) ≥Stage III vs. stage I-II (ref)

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Studies included

30,38,42,46,47,52

30,38,42,46,47

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Total events

Summary unadjusted odds ratio M-H, Random, 95% CI

38,42,46,47,52

30,46,47

996/1349

802/1183

P=0.82, I2=0%

1.13 (0.941.36)

Socioeconomic status: High vs. low (ref)

30,33,42,46,47

1121/1795

1650/2499

P=0.14, I2=43%

1.03 (0.861.25)

Marital status: Married vs. single (ref)

42,46,47

694/1276

1078/1766

P=0.17, I2=44%

0.84 (0.681.04)

Geographical region: Rural vs. urban (ref)

46,47,54

461/798

1798/2433

P=0.90, I2=0%

0.83 (0.611.12)

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Education: High vs. low (ref)

Test for overall effect: **** = P<0.00001, ***=P<0.0001, **=P<0.001, *=P<0.01; Ref = Reference. .

2.2

Study Selection

Prospective and retrospective observational studies, case-control and cross-sectional studies were included if they assessed the uptake of trastuzumab therapy in eligible HER2-positive early breast cancer or metastatic breast cancer adult patients (>16 years). The review included studies which measured outcomes directly and indirectly (e.g. self-reported). Studies were excluded if patients were HER2-negative or where information on uptake of trastuzumab

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therapy was absent. Studies which examined time to initiation, duration and completion of trastuzumab therapy were beyond the scope of this review. We excluded editorials, letters, historical articles, reviews

and abstracts published before 2010. As no evidence of a systematic bias exists from the use of Englishlanguage restrictions in systematic review-based meta-analyses in conventional medicine, this review

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included only peer-reviewed, English-language publications.20 The evidence appraisal was conducted in the context of clinical guidelines from developed countries; however evidence from developing countries was also included. Further information about our inclusion criteria is provided in Error!

Data Extraction and Quality Assessment

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2.3

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eference source not found. in Error! Reference source not found..

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Search results from databases were combined and duplicates removed. Titles and abstracts were screened to determine whether they met the pre-specified inclusion criteria by one reviewer (AM) and

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10% were double screened by a second independent reviewer (MC). Full texts were retrieved where reviewers agreed that the article met the inclusion criteria (95.6% agreement) and consensus was

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reached. After determining article inclusion, one reviewer entered study data into evidence tables (AM); a second reviewer (JD) checked 30% of data extracted for accuracy and completeness.

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Data were extracted on the following study characteristics: year of publication, study type, setting, sample population, source of information, study period, cancer status, rate of trastuzumab initiation, and reported clinical, psychosocial and sociodemographic factors. The quality of evidence was assessed

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using the Effective Public Health Practice Project (EPHPP) Quality Assessment Tool for Quantitative Studies.21 The pre-defined quality assessment criteria include six components: selection bias, study design, confounders, blinding, data collection methods, withdrawals and dropouts, and global rating. With any study where the inclusion or data quality was unclear, the study was discussed with up to two

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additional reviewers (MC and JD).

2.4

Data Synthesis and Analysis

Results are presented as summaries of individual studies. Data presented includes study type, country, age of participants, study duration, source of information, cancer status of participants and the proportion of trastuzumab uptake. In addition, a summary of associations between reported clinical, psychosocial and sociodemographic factors and uptake of trastuzumab is presented. Each association

was classified as tested and statistically significant in multivariable analyses, or tested and significant in univariable analyses, or tested and not significant. For each study, the reported proportions of patients who received or did not receive trastuzumab were included in a meta-analysis of pooled uptake. The initiation of trastuzumab therapy was largely defined as the receipt of trastuzumab therapy within one year of diagnosis. Forest plots of pooled data were prepared with RevMan V5.3 (RevMan, 2014) using the Mantel-Haenszel method and assuming a random effects model to account for heterogeneity between studies. The extent of heterogeneity was

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examined using visual inspection of data, clinical aspects, methodological aspects and the Higgin’s I2

statistic.22 Approximately, heterogeneity was classified as low, moderate and high with an I2 of 25%, 50% and 75%.23 In addition, the non-parametric Cochran’s Q test assessed statistical differences in

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proportions of uptake by matched sets. The weighted mean estimate from each study was used and 95% confidence intervals (95% CI) were calculated using normal approximation.

The uptake of trastuzumab therapy were pooled by the geographical location of each individual study

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and due to large variability in uptake by country, studies were grouped by continent. Meta-analyses

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were also conducted where the proportion of uptake were classified by subgroup of clinical, psychosocial or sociodemographic factor. Clinical factors included tumour stage, tumour grade, tumour

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size, lymph node spread, hormone receptor status, number of comorbidities, cardiovascular events,

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surgery type and year of diagnosis. Psychosocial factors included the interrelation of social factors and patient behavior. Sociodemographic factors included education level, socioeconomic status,

3. Results

Study Selection and Characteristics

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3.1

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employment, insurance coverage, marital status, age, race/ethnicity and geography.

Following removal of duplicates, a total of 2651 papers were identified by the search of electronic

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databases. A total of 107 observational studies, of which 26 met the inclusion criteria for the review and 7 additional articles were identified from a search of reference lists and citations searching which resulted in 33 studies which met the inclusion criteria. The review flow diagram and reasons for exclusion are presented in Figure 1 and the details of included studies are summarized in Error!

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Reference source not found.. Studies comprised a variety of observational research designs including retrospective cohort studies (n = 26),24,25,34–43,26,44–49,27–33 prospective cohort studies (n = 3),50–52 audits (n = 2),53,54 and cross-sectional surveys (n = 2).55,56 The results of each study quality assessment is outlined in Error! Reference source ot found. in Error! Reference source not found.. Few studies failed to meet a moderate score on one or more items of the EPHPP quality assessment checklist for quantitative studies and none of the studies which met the inclusion criteria were deemed ineligible for inclusion following quality assessment.

Seven studies received strong global ratings.33,40,42,46,47,51 Over half of the studies received moderate global ratings based on confounders (e.g. control of confounders not well described),27,28,43–45,48–50,53,54,30– 32,34,35,37,39,41

withdrawals and dropouts (e.g. did not report the number of participants who withdrew,

dropped out, or completed the study),26,38 and selection bias.25 The remaining studies received weak global ratings due to low scores on study design due to the use of cross-sectional surveys,55,56 and limited sample size may have precluded controlling for confounders.24,29,36 Overall, the quality rating for the 33 reviewed studies was moderate largely due to the features of observational study design and limited

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control of confounders in the analyses. Two of the included studies were part of the registHER study,51,52 a large prospective, multicenter, US based cohort study which described the natural history of disease

and treatment patterns for patients with HER2-positive metastatic breast cancer. Data from both studies

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were included in the results, and there is likely to be some data duplication.31,32 Similarly, data were included in our analysis from three studies that used data from the Surveillance, Epidemiology, and End

Results (SEER)-Medicare database but covered different time periods, with some overlap, and assessed

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different outcomes.42,45,47

Sample size of studies ranged from 1129 to 1928.37 Studies were from identified from 10 different

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countries, including 14 from the USA,25,27,46,47,51,52,29–33,38,42,45 five from the Netherlands,26,35,37,43,44 four

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from the UK,28,40,48,53 three from Australia34,50 and one also from New Zealand,54 two from Canada,39,49 two from Germany,41,56 one from China,36one from India24 and one from Mexico.55 Age was variably

Uptake of trastuzumab therapy for breast cancer

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3.2

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reported, but the lowest recorded was a median of 50 years24 and the highest was a median of 84 years.29

From 33 observational studies, 14,644 patients were exposed to trastuzumab therapy. Uptake of trastuzumab therapy was defined as the initiation of trastuzumab therapy following diagnosis within the

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study period. A large variability in uptake of trastuzumab in HER2-positive early breast cancer patients (9.1-100%) and metastatic breast cancer patients (50.8-84.0%) was identified. The pooled uptake

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estimate was 71.3% (95% CI 64.6-77.9), with high heterogeneity between studies (I2=99.05%, P<0.001) (Figure 2). Due to large variability in study location, studies were grouped by continent and the pooled uptake of trastuzumab was found to be higher in Australia/Oceana with 93.7% (95% CI 89.5-97.9%), followed by Europe (75.4%; 95% CI 70.0-80.8%) and North America (69.6%; 95% CI 59.7-79.5%),

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with the lowest uptake in Asia based on two studies (39.1%; 95% CI 34.9-43.3%) (P<0.001).

3.3

Subgroup analyses

As presented in Error! Reference source not found., 21 studies tested in univariate or multivariate nalyses at least one factor associated with initiation of trastuzumab and these were categorized as clinical, psychosocial or sociodemographic. Subgroup analyses of clinical factors included advanced tumour stage, tumour grade, tumour size, lymph node involvement, Charlson Comorbidity Index (CCI) score and hormone receptor status. Given an absence of evidence, subgroup analyses of psychosocial

factors was precluded. Subgroup analyses of socioeconomic factors included: age, ethnicity, education, socioeconomic status, marital status and geography. Associations between trastuzumab initiation and predictors identified are summarized in Error! Reference source not found.. Tumour stage Overall, 9 studies24,25,30,33,34,38,46–48 reported data facilitating comparison of trastuzumab initiation by tumour stage. The pooled estimate of patients with stage ≥II in comparison to stage I, indicated on average higher initiation of trastuzumab with more advanced tumour stage, although there was high

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evidence of heterogeneity between studies (combined OR 3.55, 95% CI: 2.41-5.23, P<0.00001, I2=76%). However all eight studies which compared trastuzumab initiation between stage ≥II and stage I indicated that patients with more advanced tumour stage had a higher odds of trastuzumab

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initiation.24,25,30,33,38,46–48 The pooled estimate of patients with stage ≥III in comparison to stage I-II also indicated higher initiation by more advanced tumour stage with moderate heterogeneity between studies

(combined OR 2.07, 95% CI: 1.44-2.96, P<0.0001), I2=54%) (SupplementalError! Reference source

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not found.). Of eight studies, four indicated that more advanced tumour stage had a higher odds of

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initiation30,46–48 and four were equivocal.24,25,33,38 Tumour grade

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There were 10 studies30,34,38–40,42,43,46,48,57 that reported trastuzumab initiation by tumour grade. The

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pooled estimate of patients with grade ≥2 in comparison to grade 1, indicated higher trastuzumab initiation by higher tumour grade. However, there was moderate evidence of heterogeneity between studies (combined OR 2.55, 95% CI:1.53-4.25, P=0.0003, I2=63%). Of eight studies, four

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studies38,42,46,47 indicated that patients with grade ≥1 in comparison to grade 1 had a higher odds of initiation by higher grade and four were equivocal.39,40,43,48 The pooled estimate of patients with grade

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≥3 and grade ≤2, also indicated higher uptake by higher tumour grade with high heterogeneity between studies (combined OR 1.73, 95% CI: 1.23-2.47, P<0.00001, I2=81%) (Supplemental Error! Reference source not found.). Of eight studies comparing trastuzumab initiation between grade ≥3 and grade ≤2,

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four indicated higher odds of initiation by higher grade30,46–48 and four were equivocal.38,40,43,58 Tumour size

There were 9 studies39,40,42–44,46–48,54 that reported trastuzumab initiation by tumour size. The pooled

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estimate of patients with tumour size ≥1cm in comparison to <1cm, indicated higher trastuzumab initiation by larger tumour size. There was no evidence of heterogeneity between studies (combined OR 3.16, 95% CI:2.43-4.11, P<0.00001, I2=0%). Of two studies comparing trastuzumab initiation between tumour size ≥1cm and to <1cm, one indicated a higher odds of initiation by larger tumour54 and one was equivocal.48 The pooled estimate of patients with tumour size ≥2cm in comparison to <2cm indicated higher trastuzumab initiation by larger tumour size. There was no evidence of heterogeneity between studies (combined OR 2.02, 95% CI:1.76-2.32, P<0.00001, I2=0%). Of seven

studies comparing trastuzumab initiation between tumour size ≥2cm and to <2cm, four indicated a higher odds of initiation by larger tumour40,42,46,47 and three were equivocal.39,43,44 The pooled estimate of patients with tumour size ≥3cm in comparison to <3cm also indicated higher initiation by larger tumour size (combined OR 1.80, 95% CI: 1.54-2.10, P<0.00001, I2=0%)) with no evidence of heterogeneity between studies (Supplemental Error! Reference source not found.). Of six studies comparing trastuzumab initiation between tumour size ≥3cm and to <3cm, four indicated a higher odds of initiation by larger tumour40,42,46,47 and two were equivocal.43,44

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Lymph node

There were 7 studies38–40,42,43,46,47 that reported trastuzumab initiation by tumour lymph node status. The pooled estimate of patients with node positive in comparison to node negative was not significant

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(combined OR 1.63, 95% CI: 0.95-2.80, P=0.08, I2=90%) with high evidence of heterogeneity between studies (Supplemental Figure 6). Of seven studies comparing trastuzumab initiation between node

positive and negative, four indicated a higher odds of initiation in lymph node positive patients40,42,43,46

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and three were equivocal.38,39,47

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Hormone receptor status

There were 12 studies24,25,47,48,30,33,38–40,42,43,46 that reported trastuzumab initiation by hormone receptor

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(HR) status (including estrogen receptor (ER) and progesterone receptor (PR). The pooled estimate of

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patients with HR negative status in comparison to positive, indicated higher trastuzumab initiation in patients with HR negative status (combined OR 1.55, 95% CI:1.35-1.78, P<0.00001, I2=65%) with

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moderate heterogeneity between studies. Of nine studies comparing trastuzumab initiation between HR status, four indicated a higher odds of initiation in HR negative,30,42,46,47 and five were equivocal.25,38,40,43,48 The pooled estimate of patients with ER negative status in comparison to positive

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was not significant (combined OR 1.05, 95% CI:0.74-1.50, P=0.78, I2=14%) with minimal evidence of heterogeneity between studies. Of five studies comparing trastuzumab initiation between ER status, all five were equivoval.24,25,33,39,40 The pooled estimate of patients with PR negative status in comparison

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to positive was not significant (combined OR 0.79, 95% CI:0.44-1.42, P=0.44, I2=0%) with no evidence of heterogeneity between studies (Supplemental Error! Reference source not found.). Of two studies comparing trastuzumab initiation between PR status, both were equivocal.25,40

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Comorbidities

There were 6 studies30,33,38,42,43,47 that reported trastuzumab initiation by CCI score. The pooled estimate of patients with CCI =0 in comparison to >0, indicated higher trastuzumab initiation by patients with a lower CCI score with moderate evidence of heterogeneity between studies (combined OR 1.62, 95% CI:1.32-1.99, P<0.00001, I2=29%). Of six studies comparing trastuzumab initiation between CCI =0 and >0, three indicated higher odds of initiation in patients with a CCI score equal to zero30,42,43 and three were equivocal.33,38,47 The pooled estimate of patients with CCI 0-1 in comparison to >1, indicated

higher uptake of trastuzumab by patients with a lower CCI score (combined OR 1.52, 95% CI:1.22-

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1.88, P=0.0001, I2=0%) with no evidence of heterogeneity between studies (Supplemental

Figure 8). Of five studies comparing trastuzumab initiation between CCI 0-1 and >1, two indicated higher odds of initiation in patients with a lower CCI score30,42 and three were equivocal.33,43,47 Treatment characteristics Although not included in meta-analyses, three studies found that more recent year of diagnosis was a predictor of higher initiation of trastuzumab therapy30,42,46 and one study found year of diagnosis was equivocal.37 Whitfield et al (2012)54 found a positive association between surgeon caseload and trastuzumab initiation. Reeder-Hayes et al (2016)42 found that patients were more likely to initiate

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trastuzumab therapy if patients received breast conserving surgery compared to mastectomy but found an inverse relationship if breast conserving surgery was delivered in combination with radiotherapy.

Further, the study did not identify a significant association between trastuzumab initiation in patients

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who had a mastectomy and patients who had a mastectomy in combination with radiotherapy. In a study by Seferina et al. (2015), mastectomy versus breast conserving strategy, breast conserving versus no

surgery, receipt of adjuvant endocrine therapy, and receipt of radiotherapy were not predictors of

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trastuzumab initiation.43 Noonan et al. (2012)39 also failed to identify a significant relationship between trastuzumab initiation and receipt of radiotherapy. Seferina et al. (2015)43 found that there was a

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significant positive association between receipt of neoadjuvant chemotherapy and trastuzumab

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initiation. Neugut et al. (2014)38 found that recommendation for chemotherapy and use of adjuvant chemotherapy were predictors of trastuzumab initiation. Noonan et al. (2012)39 did not identify a

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non-anthracycline-based chemotherapy.

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significant relationship between trastuzumab initiation in patients receiving anthracycline-based versus

Age

There were 10 studies30,33,38,40,41,43,46,47,51,54 that reported trastuzumab initiation by age of patient. The

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pooled estimate of younger patients less than 50 years in comparison to patients older than 50 years, indicated that as age increased, initiation reduced but there was high heterogeneity between studies (combined OR 2.15, 95% CI:1.58-2.92, P<0.00001, I2=68%). Of eight studies comparing trastuzumab

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initiation between <50 years and ≥50 years, six indicated a higher odds of initiation in younger patients30,40,41,43,46,54 and two were equivocal.33,38 The pooled estimate of younger patients less than 60 years in comparison to patients older than 60 years, found that as age increased, initiation reduced

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(combined OR 2.59, 95% CI:1.88-3.56, P<0.00001, I2=71%) with high heterogeneity between studies. Of seven studies comparing trastuzumab initiation between <60 years and ≥60 years, six indicated a higher odds of initiation in younger patients30,38,40,41,43,54 and one was equivocal.46 The pooled estimate of patients less than 70 years in comparison to patients older than 70 years, found that as age increased, initiation reduced (combined OR 3.90, 95% CI:2.53-6.03, P<0.00001, I2=81%) with high heterogeneity between studies (Supplemental Error! Reference source not found.). Of six studies comparing

trastuzumab initiation between <70 years and ≥70 years, four indicated a higher odds of initiation in younger patients30,41,47,54 and two were equivocal.38,51 Ethnicity There were 6 studies30,38,42,46,47,52 that reported trastuzumab initiation by ethnicity of patient. The pooled estimate of white patients in comparison to black patients was not significant (combined OR 1.26, 95% CI:0.92-1.72, P=0.16, I2=38%) with low heterogeneity between studies. Of six studies comparing trastuzumab initiation between white and black patients, one study indicated a higher odds of initiation

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in white patients47 and five were equivocal.30,38,42,46,52 The pooled estimate of white patients in comparison to other patients was not significant (combined OR 0.82, 95% CI:0.66-1.10, P=0.06, I2=0%,) with no evidence of heterogeneity between studies. Of five studies comparing trastuzumab

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initiation between white and other patients, all five were equivocal.30,38,42,46,47 The pooled estimate of white patients in comparison to non-white (including ‘black’, ‘Latina’ and ‘Asian’) patients was not

significant (combined OR 0.99, 95% CI:0.79-1.24, P=0.90, I2=44%) with low heterogeneity between

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studies (Supplemental Figure 10). Of six studies comparing trastuzumab initiation between white and non-white patients, one study indicated a higher odds of initiation in non-white patients and five studies

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were equivocal.38,42,46,47,52

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Education

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There were 3 studies30,46,47 that reported trastuzumab initiation by education status of patient. The pooled estimate of patients with more education in comparison to less education was not significant (combined

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OR 1.13, 95% CI:0.94-1.36, P=0.19, I2=0%) with no evidence of heterogeneity between studies (Supplemental Figure 11). Of three studies comparing trastuzumab initiation between higher educated

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and less, all were equivocal. 30,46,47 Socioeconomic status

There were 5 studies30,33,42,46,47 that reported trastuzumab initiation by socioeconomic status of patient.

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The pooled estimate of economically advantaged patients in comparison to deprived patients was not significant (combined OR 1.03, 95% CI:0.86-1.25, P=0.74, I2=43%) with low heterogeneity between

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studies (Supplemental

Figure 12). Of five studies comparing trastuzumab initiation between economically advantaged and disadvantaged, all were equivocal.30,33,42,46,47 Marital status There were 3 studies42,46,47 that reported trastuzumab initiation by marital status of patient. The pooled estimate of married patients in comparison to single patients was not significant (combined OR 0.84, 95% CI:0.68-1.04, P=0.11, I2=44%) with low heterogeneity between studies (Supplemental Error! Reference source not found.). Of three studies comparing trastuzumab initiation between married and

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single, one study indicated a higher odds of initiation in married patients 47 and two studies were equivocal.42,46

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Geography

There were 3 studies46,47,54 that reported trastuzumab initiation by geography in terms of urban or rural location. The pooled estimate of rural initiation in comparison to urban initiation was not significant (combined OR 0.83, 95% CI:0.61-1.12, P=0.23, I2=0%) with low heterogeneity between studies

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(Supplemental Figure 14). Of three studies comparing trastuzumab initiation between urban and rural

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location, all were equivocal.46,47,54 Although not included in meta-analysis across five other studies, geographical location of care facility was a significant predictor of trastuzumab initiation in three

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studies30,36,37 and equivocal in two other studies.33,42

4. Discussion

This study identified variability in trastuzumab initiation in HER2 positive breast cancer patients, both

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between study settings and within studies. The presence of comorbidities and lower disease burden in terms of lower stage, lower grade and smaller tumour size were found to be associated with significantly

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lower trastuzumab initiation. Further, therapy initiation was also found to be significantly lower in hormone receptor positive patients. In terms of patient sociodemographics, this review did not identify any significant association in trastuzumab initiation by ethnicity, education status, socioeconomic

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status, marital status and geographical region. However, older age was found to be significantly associated with lower initiation. According to ASCO and ESMO guidance, in special circumstances, such as low disease burden

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(dependent on tumour stage, grade and size), presence of comorbidities, and/or presence of a long disease-free interval, clinicians may offer first-line endocrine therapy only.10,59 There has been debate on the necessity for trastuzumab-based chemotherapy in patients with low disease burden (T1N0),60 but a meta-analysis of trastuzumab trials has shown that this patient groups derives clinically relevant treatment benefit.61 Therefore in accordance with guidance, clinicians are recommended to provide HER2-targeted therapy based combinations for first-line treatment.

Pivotal trials (HERA trial,62 the BCIRG 006 trial,63 and N9831/B-315,64) found that patients, regardless of age, lymph node status, menopausal status or hormone status saw an increase in disease-free survival.65 It has also been recommended that large post-registration studies are conducted as subgroups, such as node negative patients were underrepresented in trials (HERA and (BCIRG)-006) and in randomized trials, a high proportion of tumors tended to be more aggressive than those seen in clinical practice.30,60,66,67 Underrepresentation of elderly populations in clinical trials is widely reported and our study also found

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that age was associated with lower initiation of therapy, with patients under 50 years old being 2.15

times more likely than those over 50 years to start trastuzumab therapy. The odds were even higher with

patients older than 60 and 70 years. This is consistent with the fact that older breast cancer patients are

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less likely to receive adjuvant chemotherapy despite the fact that older patients benefit to an equivalent

extent from adjuvant chemotherapy as younger patients.68 Given the sizeable treatment benefit from trastuzumab therapy and the aggressive biology of HER2-expressing tumours, ESMO have

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recommended that despite absence of evidence from randomized studies, treatment decisions should be

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based on biological factors.10

According to SEER data, in the USA, approximately 50% of diagnosed breast cancer patients are 65

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years or older and 35% are 75 years or older.69 Yet in clinical trials and in published studies, the overall

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proportion of patients older than 60 years was approximately 10% and subgroup analyses by age has largely been poorly reported.70 While the HERA study had comparatively unrestricted inclusion criteria,

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the proportion of patients older than 60 years was only 16.2%, diverging from the typical population served in routine clinical practice.60 Larger studies which reflect the entire age spectrum of patients are

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needed to determine safety and efficacy within older and also comorbid patients.54 Before initiation of therapy, many patients need to undergo primary breast surgery and therefore need to be sufficiently fit for surgery. As elderly patients are likely to have co-morbidities, and therefore may

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not be fit for surgery, this may be one reason for the lower usage of trastuzumab in the elderly. Another reason for the lower use of trastuzumab in older patients may be its potential to cause cardiotoxicity; in the Slamon et al. phase III trial,3 cardiac events were reported in 27% and congestive heart failure (CHF) was reported in 16% of metastatic breast cancer patients treated concurrently with anthracyclines. A

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recent meta-analysis found that trastuzumab induced cardiotoxicity (TIC) occurred in 12% (CI: 11.312.9%) of patients and age, hypertension, diabetes and previous anthracycline use were identified as risk factors for TIC.71 Therefore, older patients may be less likely to receive therapy to avoid exposure to a potentially cardiotoxic treatment, especially if there is underlying cardiovascular comorbidity. Thus, while our findings may suggest that there is inequity of access with older age, this may not be the case as there may have been good clinical reasons to avoid the use of trastuzumab in older patients. An

individual patient data meta-analysis would be required to determine the likely reasons for lower use of trastuzumab in the elderly. While findings from this review did not reveal consistent disparities in uptake of targeted-therapy by ethnicity, there remains a general underrepresentation of research in diverse ethnic groups.72 Indeed, evidence from one study identified disparities by ethnicity, despite the presence of a clear biologic predictor of treatment benefit.47 In the USA between 2000 and 2010, breast cancer mortality decreased annually by 2%, primarily due to earlier diagnosis and improved treatment strategies, 52,73,74 although

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this decline was slower in black patients and a widening disparity ratio in breast cancer mortality was

observed between white and black patients increasing from 30.1% to 41.8%.73,75 Furthermore, to successfully address the persistent mortality gap in minority patients, and given their

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underrepresentation in clinical trials, additional research into underlying tumor and host biology is needed to improve treatment response.

Treatment disparities remain despite widespread efforts to improve access to care among minority

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groups. One study found that 8% of breast cancers were reported at an advanced stage in black patients

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compared to 5% in white patients and delayed diagnosis resulted from lower frequency of mammograms, longer waiting times between mammograms and less consistent follow-up of suspicious

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mammogram results among black patients in the USA.76 Within Europe, concerns have been raised

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regarding challenges in funding the HER2 test which also may have impacted trastuzumab utilization.77 Studies have also found that following diagnosis, black patients with HER2 positive metastatic breast cancer have poorer prognostic factors and independently worse clinical outcomes than white

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patients.52,76 Another study found that of patients diagnosed with small breast tumors (≤2cm) during 2004 and 2011, 24% of black patients and 18% of white patients were likely to present with lymph node

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metastases.15 Therefore, disparities in mortality may exist in part due to later stage diagnosis, but also poorer stage specific survival due to greater prevalence of aggressive subtypes of cancer in black

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patients.78,79

Trastuzumab is an expensive therapy and aspects of health care delivery may contribute to underuse in deprived populations.80 Even for insured patients, the burden of care may be significant due to outpatient expenses and thus, lack of affordability may be associated with factors such as age, education and race.42

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Moreover, in some lower-middle income countries where trastuzumab has been provided for a relatively small numbers of patients, trastuzumab has contributed appreciably to the financial burden of health care.81,82 Within the USA, the burden of cancer care is evident as some patients have had to sell their homes to provide funding.83 Pricing of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs which has been challenged by leading CML experts and oncologists.84 Consequently, issues of affordability affect not only lower-middle income countries but also higher income countries. However, following patent expiry, biosimilars may provide more

financially accessible alternatives; however, greater efforts are needed to address barriers faced by patients.

Further, trastuzumab therapy is typically recommended for a duration of 12 months.9,10 As such, the pairing of trastuzumab with intensive chemotherapy regimens and long duration of treatment may be a significant barrier to patients with limited transport options, employment uncertainty, poor support

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network and this may be combined with a preconception from providers that patients identified as

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vulnerable, may be less able to tolerate and complete therapy.30,42

. Further research is needed into other aspects of the care pathway of trastuzumab therapy as disparities have been identified in time to initiation,85 duration86–89 and completion26,30,38,44,50,69,90–92 of therapy. Disparities in long term adherence have been found to be associated with ethnicity,85,92 socioeconomic

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status,36 education attainment,30,92 employment and insurance status.30 These differences in treatment

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duration and completion may have been amplified by the need for frequent infusions over a prolonged

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period. While it is possible that patients may benefit from shorter durations of therapy,93 this has not been well studied, and guidelines recommend one year of therapy for all patients, until disease

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progression and/or unacceptable toxicity.59,94

This review has identified a pattern of care delivery which requires further exploration to ensure

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equitable access in clinical practice. However, relevant comorbidities, and cardiac risk factors vary by subgroup, and therefore initiation of trastuzumab therapy may be influenced by a number of

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confounders which is a limitation in the assessment of uptake in observational studies. In addition, while the treatment regimens may reflect local clinical practice, these studies may not be representative of

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general clinical practice due to sample selection bias. The meta-analyses presented in this paper identified substantial heterogeneity that could be attributed to methodological and/or clinical variations in the characteristics of the included studies. Moreover, changing patterns of therapy delivery, scheduling, and settings could have resulted in differences in

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uptake at different time periods. Furthermore, it is also possible that some of the findings may be due to factors unique to each study and which could not be identified by means of a systematic review or meta-analysis. A limitation specific to this review is that screening may have failed to identify relevant studies which did not comment on initiation of trastuzumab therapy in the title or abstract. In addition, studies did not address the full range of factors which may explain underuse of therapy in certain groups of patients

and psychosocial factors remain understudied. Further, included studies focused on HER2 positive patients but the proportion of HER2 borderline patients and how therapy varied was not extracted. In addition, information on why patients were not selected for trastuzumab therapy was not consistently described and thus precluded from this review. Additional research should examine prescribing behavior at the provider level to explore other stakeholder factors, as well as explore other inequalities in the HER2 positive breast cancer care pathway, such as receipt of chemotherapy and hormone therapy.58,95

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5. Conclusion

Trastuzumab is a pioneering therapy with important treatment benefits for HER2 positive breast cancer

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patients. This review has demonstrated that disparities in initiation of trastuzumab therapy exist

dependent on disease burden, comorbidities and age of patients. These findings may have wider implications for other targeted therapies. Further research is needed to address unequal access to high quality treatments, delay from diagnosis to treatment and disparities in therapy completion.

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System-level interventions that identify eligible patients objectively and consistently, as well as

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interventions that focus on removing barriers to therapy at the patient and provider level are needed to ensure treatment reaches deprived populations. Studies assessing individual level data are needed to

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better characterize factors underlying disparities in breast cancer treatment. Fortunately, the increasing

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effectively assess accessibility.

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use of electronic data records provides an opportunity to better identify eligible patients and more

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Ethical approval: Not needed

Disclaimer: This study was supported by the National Institute of Health Research Collaboration for Leadership in Applied Health Research and Care North West Coast (NIHR CLAHRC NWC). The

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investigators were solely responsible for the content and the decision to submit the manuscript for publication. The funding source had no role in the selection, critical appraisal, or synthesis of evidence. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the

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Department of Health.

Conflict of interest statement: This study was supported by the National Institute of Health Research Collaboration for Leadership in Applied Health Research and Care North West Coast (NIHR CLAHRC NWC). The investigators were solely responsible for the content and the decision to submit the manuscript for publication. The funding source had no role in the selection, critical appraisal, or synthesis of evidence. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The authors have no further conflicts of interest to declare.

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Tsai H, Isaacs C, Lynce F, O’Niell S. Initiation of Trastuzumab by Women Younger Than 64 Years for Adjuvant Treatment of Stage I-III Breast Cancer. J Natl Compr Canc Netw. 2017;5:601-607.

47.

Nancy IV, Nancy UL, Barry WT, et al. Treatment of early-stage human epidermal growth factor 2-positive cancers among medicare enrollees : age and race strongly associated with non-use of trastuzumab. Breast Cancer Res Treat. 2016;159(1):151-162. doi:10.1007/s10549016-3927-4

Webster RM, Abraham J, Palaniappan N, Caley A, Jasani B. Exploring the use and impact of adjuvant Trastuzumab for HER2-positive breast cancer patients in a large UK cancer network Do the results of international clinical trials translate into a similar benefit for patients in South East Wales ? Br J Cancer. 2012;106(1):32-38. doi:10.1038/bjc.2011.506

49.

Zurawska U, Baribeau D, Giilck S, et al. Outcomes of her 2 -positive early-stage breast cancer in the trastuzumab era: a population-based study of Canadian patients. Curr Oncol. 2013;20:e539-545.

50.

Chan A, Mcgregor S. Prevalence and management of HER2/neu-positive early breast cancer in a single institution following availability of adjuvant trastuzumab. Intern Med J. 2011;42(3):267-274. doi:10.1111/j.1445-5994.2011.02432.x

51.

Kaufman P, Brufsky A, Mayer M, Rugo H, Tripathy D. Treatment patterns and clinical outcomes in elderly patients with HER2-positive metastatic breast cancer from the registHER observational study. Breast Cancer Res Treat. 2012;135:875-883. doi:10.1007/s10549-0122209-z

52.

Rugo HS, Brufsky AM, Ulcickas M. Racial disparities in treatment patterns and clinical outcomes in patients with HER2-positive metastatic breast cancer. Epidemiology. 2013;141:461-470. doi:10.1007/s10549-013-2697-5

53.

Marla S, Cardale J, Dodwell DJ, et al. A multicentre audit of HER2 positive Early Breast Cancers and the reasons why patients do not receive trastuzumab therapy. Eur J Cancer Suppl. 2010;8(3):85-86. doi:10.1016/S1359-6349(10)70125-7

54.

Whitfield R, Kollias J, Silva P De, Zorbas H, Maddern G. Use of trastuzumab in Australia and New Zealand : results from the. ANZ J Surg. 2012;82:234-239. doi:10.1111/j.14452197.2011.05998.x

55.

Chavarri-guerra Y, Louis J, Liedke P, et al. Access to care issues adversely affect breast cancer patients in Mexico : oncologists ’ perspective. BMC Cancer. 2014;14(658):1-8.

56.

Liebrich C, Unger G, Dlugosch B, Hofmann S, Petry K. Breast Care Adopting Guidelines into Clinical Practice : Implementation of Trastuzumab in the Adjuvant Treatment of Breast Cancer in Lower Saxony, Germany, in 2007. Breast Care. 2011;6:43-50. doi:10.1159/000324048

57.

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58.

Reeder-hayes KE, Meyer AM, Drive D, Hill C, Wheeler SB. Racial disparities in initiation of adjuvant therapy of early breast cancer. Breast Cancer Res Treat. 2014;145(3):743-751. doi:10.1007/s10549-014-2957-z.Racial

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Dall P, Koch T, Gohler T, Selbach J, Ammon A. Trastuzumab in Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: Results of a Prospective, Noninterventional Study on Routine Treatment Between 2006 and 2012 in Germany. Oncologist. 2017;22:131138.

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Smith I, Procter M, Gelber RD, et al. 2-year follow-up of trastuzumab after adjuvant

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Perez EA, Romond EH, Suman VJ, et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014;32(33):3744-3752. doi:10.1200/JCO.2014.55.5730

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Mackey J, McLeod D, Ragaz J, et al. Adjuvant targeted therapy in early breast cancer. Cancer. 2009;115(6):1154-1168. doi:10.1002/cncr.24114

66.

Denegri A, Moccetti T, Moccetti M, Spallarossa P, Brunelli C, Ameri P. Cardiac toxicity of trastuzumab in elderly patients with breast cancer. J Geriatr Cardiol. 2016;13:355-363. doi:10.11909/j.issn.1671-5411.2016.04.003

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Snider J, Ahmed C, Paba G, Phelps C, Verrier L. Cardiotoxicity of Trastuzumab Treatment in African American Women and Older Women in the Non Trial Setting. Cancer Res. 2009;69(24).

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Burdette-radoux S, Muss HB, Allen F, Care H. Adjuvant Chemotherapy in the Elderly: Whom to treat, what regimen? Oncologist. 2006;11:234-242. doi:10.1634/theoncologist.11-3-234

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Rooijen JM Van, Munck L De, Teeuwen GM, et al. Use of trastuzumab for HER2-positive metastatic breast cancer in daily practice : a population-based study focusing on the elderly. Anticancer Drugs. 2016;27(2):127-132. doi:10.1097/CAD.0000000000000310

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Brollo J, Curigliano G, Disalvatore D, et al. Adjuvant trastuzumab in elderly with HER-2 positive breast cancer: A systematic review of randomized controlled trials. Cancer Treat Rev. 2013;39(1):44-50. doi:10.1016/j.ctrv.2012.03.009

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Jawa Z, Perez RM, Garlie L, et al. Risk factors of trastuzumab-induced cardiotoxicity in breast cancer. Medicine (Baltimore). 2016;95(44):1-7.

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Armstrong K. Equity in precision medicine: Is it within our reach? JNCCN J Natl Compr Cancer Netw. 2017;15(3):421-423.

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Ma H, Lu Y, Malone KE, et al. Mortality risk of black women and white women with invasive breast cancer by hormone receptors , HER2 , and p53 status. BMC Cancer. 2013;13(225):1-11.

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Daly B, Olopade OI. A perfect storm: How tumor biology, genomics, and health care delivery patterns collide to create a racial survival disparity in breast cancer and proposed interventions for change. CA Cancer J Clin. 2015;65(3):221-238. doi:10.3322/caac.21271

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85.

Nancy IV, Nancy UL, Barry WT, et al. Racial differences in outcomes for patients with metastatic breast cancer by disease subtype. Breast Cancer Res Treat. 2015;151(3):697-707. doi:10.1007/s10549-015-3432-1

86.

Haq R, Gulasingam P. Duration of trastuzumab in patients with HER2-positive metastatic breast cancer in prolonged remission. 2016;23(2):91-95.

87.

Tsai H, Isaacs C, Fu A, JL W, Freedman A. Risk of cardiovascular adverse events from trastuzumab (Herceptin®) in elderly persons with breast cancer: a population-based study. Breast Cancer Res Treat. 2014;144(1):163-170. doi:10.1007/s10549-014-2836-7

88.

Ansaripour A, Groot CAU, Foroozanfar M, Rahimimoghadam S, Redekop WK. Which is more important for doctors in a middle-income country , a national guideline or the medical literature ? An adherence survey of trastuzumab use for breast cancer in Iran. J Cancer Policy. 2016;9:8-13. doi:10.1016/j.jcpo.2016.05.005

89.

Moga S, Juhasz S, Bardens D, et al. Trastuzumab (herceptin): a retrospective analysis of the effects of long ‑ term application in a series of patients with breast cancer. Arch Gynecol Obs. 2014;290:733-739. doi:10.1007/s00404-014-3261-1

90.

Montserrat M, Leveque D, Barthelemy P, Bergerat J. Duration of Adjuvant Trastuzumab Treatment in Routine Practice. Anticancer Res. 2012;32:4585-4588.

91.

Wang S, Long J, Hurria A, et al. Cardiovascular events , early discontinuation of trastuzumab, and their impact on survival. Breast Cancer Res Treat. 2014;146:411-419. doi:10.1007/s10549-014-3029-0

A

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A

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79.

92.

Vaz-luis I, Keating NL, Lin NU, et al. Duration and Toxicity of Adjuvant Trastuzumab in Older Patients With Early-Stage Breast Cancer : A Population- Based Study. J Clin Oncol. 2014;32(9):927-935. doi:10.1200/JCO.2013.51.1261

93.

Kramar A, Bachelot T, Madrange N, et al. Trastuzumab duration effects within patient prognostic subgroups in the PHARE trial. Ann Oncol. 2014;25(May 2014):1563-1570. doi:10.1093/annonc/mdu177

94.

Denduluri N, Somerfield MR, Eisen A, et al. Selection of optimal adjuvant chemotherapy regimens for human epidermal growth factor receptor 2 (HER2) -negative and adjuvant

targeted therapy for HER2-positive breast cancers: An American Society of Clinical Oncology Guideline Adaptation of the Cancer C. J Clin Oncol. 2016;34(20):2416-2427. doi:10.1200/JCO.2016.67.0182 Livaudais JC, Hershman DL, Habel L, et al. Racial/ethnic differences in initiation of adjuvant hormonal therapy among women with hormone receptor-positive breast cancer. Epidemiology. 2012;131:607-617. doi:10.1007/s10549-011-1762-1

A

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95.

Figures

Additional records identified through other sources (n = 14)

IP T

Records identified through database searching (n = 3968)

M

A

N

Records screened (n = 2651)

U

Screening

Records after duplicates removed (n = 2651)

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Identification

Figure 1 PRISMA flow diagram displaying articles included and excluded in this review

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Included

Eligibility

Full-text articles assessed for eligibility (n = 107)

   

Studies included for review (n = 33)

 

Records excluded (n = 2544)

Full-text articles excluded (n = 74) Not HER2 positive (n = 6) Uptake, utilisation, access, inequalities or barriers not discussed (n = 19) Differences in treatment duration or completion (n = 20) Not relevant publication type (excluding letters, case reports, editorials and conference abstracts before 2010 (n = 10) Duplicate (n = 9) Other reason (n = 10)

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Figure 2 Meta-analysis of individual-level data for trastuzumab therapy uptake by continent

Appendix 3

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Figure 3 Odds ratios of trastuzumab therapy initiation by later tumour stage in comparison with earlier

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Figure 4 Odds ratios of trastuzumab therapy initiation by higher tumour grade status in comparison with lower

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Figure 5 Odds ratios of trastuzumab therapy initiation by larger tumour size in comparison with smaller

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Figure 6 Odds ratios of trastuzumab therapy initiation by positive node status in comparison with negative

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Figure 7 Odds ratios of trastuzumab therapy initiation by hormone receptor positive in comparison with negative

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Figure 8 Odds ratios of trastuzumab therapy initiation by lower Charlson Comorbidity Index Status in comparison with higher

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Figure 9 Odds ratios of trastuzumab therapy initiation by younger age group in comparison with older

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Figure 10 Odds ratios of trastuzumab therapy initiation by white ethnic group in comparison with other

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Figure 11 Odds ratios of trastuzumab therapy initiation by higher education status in comparison with lower

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Figure 12 Odds ratios of trastuzumab therapy initiation by lower socioeconomic status in comparison with higher

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Figure 13 Odds ratios of trastuzumab therapy initiation by single marital status in comparison with married

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Figure 14 Odds ratios of trastuzumab therapy initiation by rural geography in comparison with urban

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Tables Table 1 Summary of studies included in review Reference

Study type

Country

Adusumilli et al. (2017) Barron et al. (2009) Boons et al. (2016) Byfield et al. (2016) Chan and McGregor (2012)

Retrospective cohort study Retrospective cohort study Retrospective cohort study Retrospective cohort analysis Prospective cohort study

India

ChavarriGuerra et al. (2014) Coulson et al. (2010)

Cross-sectional survey

Source of information

Cancer status

TTT initiation

Private payment for therapy, Department of Medical Oncology, Nizam’s Institute of Medical Sciences, Hyderabad, Telangana Administrative health claims from three commercial health plans located in westem and southeastern U.S 7 randomly selected Dutch hospitals (3 general hospitals, 2 top clinical hospitals, 1 academic hospital, and 1 specialized oncology hospital) Physician-reported data for insured patients, Oncology Management Registry linked with Optum Research Database Private hospital, Mount Hospital

EBC

76/212 (35.8%)c

MBC

51/72 (70.8%)d

EBC MBC EBC

EBC: 147/160 (91.9%)c MBC: 75/91 (82.4%)c 662/915 (72.3%)d

EBC

Private hospital: 110/110 (100.0%)c Other setting: 13/25 (52.0%)c <1 cm tumors: 54.3%c >1 cm tumors: 77.5%c

56 (2990)

Mexico

-

-

Web-based survey of Mexican Oncologists (18.6% response)

BC

UK

68 (3491)

September 2007 to August 2008

North Trent Cancer Network

EBC

1 January 1998 to 30 June 2009 September 2005 to December 2009 1 January 1998 to 31 December 2007

John Cochran Veterans Hospital, St. Louis, Missouri

EBC

USA

84 (8096) -

129/185 (69.7%)d 4/14 (28.6%) borderline HER2+d 1/11 (9.1%)c

NCCN Breast Cancer Outcomes Database Project

EBC

920/1109 (83.0%)f

Kaiser Permanente Northwest (KPNW), Oregon and Southwest Washington

EBC MBC

1 January 1999 to 31 December 2007 1 July 2006 to 30 June 2008 2008 to 2011

KPNW Oregon and Southwest Washington Claims from large national health plan, Aetna, Hartford, CT

EBC MBC EBC

1998-2004: 35/366 (9.6%)c 2005-2007: 71/130 (54.6%)c 1999-2005: 33/63 (52.4%)c 2006-2007: 28/33 (84.8%)c 79/137 (57.7%)c

Four Sydney-based cancer centers

EBC

168/176 (86.7%)c

1 January 2000 to 31 December 2008

Eindhoven Cancer Registry linked to the PHARMO Record

BC

December 2003 to February 2006

registHER study

MBC

Adjuvant chemo 43/58 (74.1%)c Palliative chemo 22/24 (91.7%)c 841/1001 (84.0%)c

52 (SD 9)

ED

USA

M

Netherlands

A

Australia

USA

Cyr et al. (2011) Freedman et al. (2013) Goddard et al. (2012)a

Retrospective cohort study Retrospective cohort study Retrospective cohort study

USA

USA

-

Goddard et al. (2012)a Haas et al. (2011) Harris et al. (2013) Herk-sukel et al. (2013)

Retrospective cohort study Retrospective cohort study Retrospective cohort study Retrospective cohort study

USA

-

USA

54 (3565) 55 (2191) 48.8 (-)b

Kaufman et al. (2012)a

Prospective cohort study

USA

A

Study period time

January 2007 to December 2013 1 June 2005 to 30 June 2006 June 2008 to December 2009 1 January 2008 to 31 August 2013 1 October 2006 to 31 March 2009

PT

CC E

Retrospective cohort study

Mean age (range) 50 (2776) 53.8 (SD 10.9) -

Australia Netherlands

54.6 (2092)b

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China

-

2010 to 2015

13 hospitals in Eastern China

Germany

57.4 (2089) -

2007

Retrospective cohort study

Netherlands

60 (21101)

Neugut et al. (2014) Noonan et al. (2012) Palmieri et al. (2011)

Retrospective cohort study Retrospective cohort study Retrospective cohort study

USA

56.0 (4079)b 56 (-)

Peters et al. (2015) Reeder-Hayes et al. (2016) Rugo et al. (2013)a Seferina et al. (2015)a Seferina et al. (2016)a Stenehjem et al. (2014)a Tsai et al. (2017) Vaz-Luis et al. (2016)a Webster et al. (2012) Whitfield et al. (2012)

Retrospective cohort study Retrospective cohort study Prospective cohort study Retrospective cohort study Retrospective cohort study Retrospective cohort study Retrospective cohort study Retrospective cohort study Retrospective cohort study Audit

Germany

52.3 (31.180.7) 64 (-)b

USA USA

Zurawska et al. (2013)

Retrospective cohort study

A

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Canada UK

2007 to 2008

Six UK hospitals

EBC

238/386 (61.7%)c

September 2005 to January 2007

Netherlands Cancer Registry

EBC

May 2006 and June 2010 January 2005 to January 2010 January 2006 and December 2008

BQUAL study: New York City

EBC

1057/1928 (54.8%)c 1057/1114 (94.9%) (with adjuvant chemotherapy)c 119/152 (78.3%)c

Newfoundland and Labrador Provincial Tumour Registry

EBC

113/148 (76.4%)c

Imperial College Healthcare NHS Trust

EBC

128/177 (72.3%)c

2006 to 2013

Patients’ Tumor Bank of Hope database

EBC

255/331 (77.0%)c

75.4 (-)b

2009 to 2013

EBC

672/690 (97.4%)f

53.5 (2093) 51 ( 27– 72) -

December 2003 to February 2006 January 2005 to December 2007 January 2005 to December 2007 1 January 2005 to 31 December 2012 2006 to 2011

Surveillance, Epidemiology, and End Results SEER-Medicare–linked data set registHER study

MBC

772/919 (84.0%)g

Five Dutch hospitals in southeast Netherlands

EBC

196/251 (78.1%)c

Five Dutch hospitals in southeast Netherlands

EBC

Huntsman Cancer Institute Tumor Registry, SEER reporting registry, Utah

EBC

230/269 (85.5%) (with adjuvant chemotherapy)c 186/245 (75.9%)c

Cancer registry and claims-linked data set

EBC

680/934 (72.8%)e

2011 to 2013

SEER Medicare database

EBC

428/770 (55.6%)e

1 January 2005 to 31 December 2008 January 2006 to December 2008

South East Wales Cancer Network

EBC

237/336 (70.5%)c

Royal Australasian College of Surgeons – National Breast Cancer Audit

EBC

1 January 2005 to 31 December 2006

Odette Cancer Centre, Toronto, Ontario

EBC

2006 - 356/707 (50.4%) 2007 - 474/714 (66.4%) 2008 - 668/908 (73.6%)f 76/94 (80.9%)c

M

UK

ONkeyLINE (voluntary tumour registry), Lower Saxony

EBC: 412/1017 (40.5%)c MBC: 366/720 (50.8%)c 334/433 (77.1%)f

ED

Liebrich et al. (2007) Marla et al. (2010) Munck et al. (2011)

EBC MBC EBC

A

Retrospective cohort study Cross-sectional survey Audit

PT

Li et al. (2017)

Netherlands Netherlands USA

USA

57 (SD 13)c 49.9 (2463)b 75.4 (-)b

Wales - UK

-

Australia and New Zealand

-

Canada

53 (40.965.1)

USA

BC, breast cancer; EBC, early breast cancer; MBC, metastatic breast cancer. a Research conducted in same cohort. b Weighted mean calculated from group averages. c Receipt of trastuzumab within study period d Receipt of trastuzumab within 6 months of diagnosis e Receipt of trastuzumab within first 9 months of diagnosis f Receipt of trastuzumab within 1 year of diagnosis

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g Receipt of trastuzumab-based first-line regimens (>=21 days of trastuzumab in first-line therapy) prior to first disease progression f Receipt of trastuzumab (defined as having start date for trastuzumab at any time after diagnosis but before any recurrence)

Page 40 of 44

A

CC E Lymph nodes (positive/number) Hormone receptor status (ER/PR) Comorbidity (CCI)

Menopause

Year of diagnosis

Caseload of surgeon Mastectomy vs. breast conserving Mastectomy vs. mastectomy and radiation Mastectomy vs. mastectomy and radiation Mastectomy vs. lumptectomy Adjuvant endocrine/hormon al therapy Chemotherapy anthracycline- vs. non-anthracyclinebased Adjuvant radiotherapy Adjuvant chemotherapy Neoadjuvant chemotherapy ✓

Tumour size

~

✓ ~

~

ED

PT

Tumour stage

Tumour grade ~ ✓✓

✓✓

Chavarri-Guerra et al. (2014)

Harris et al. (2013)

~ ✓

~ ~

✓✓ ~ ~

Webster et al. (2012)

✓ ✓ ~ ~

✓ ~ ~ ✓✓ ~ ✓ ✓✓ ~

~ ✓ ✓✓ ✓ ✓ ~ ~

~ ✓ ✓ ✓✓ ✓ ✓ ~

~ ~ ~ ~ ~ ✓ ✓✓

~ ✓✓ ✓ ~ ~

✓✓

~ ~

✓ ✓✓

✓✓ ✓

~

Zurawska et al. (2013)

Whitfield et al. (2012)

Tsai et al. (2017)

Stenehjem et al. (2014)

Seferina et al. (2016)

Seferina et al. (2015)

Rugo et al. (2013)

Reeder-Hayes et al. (2016)

Peters et al. (2015)

Palmieri et al. (2011)

Vaz-Luis et al. (2016)

~

Noonan et al. (2012)

~

Neugut et al. (2014)

Munck et al. (2011)

Marla et al. (2010)

Liebrich et al. (2007)

Li et al. (2017)

Kaufman et al. (2012)

Herk-sukel et al. (2013)

Haas et al. (2011)

Goddard et al. (2012)

Goddard et al. (2012)

N U SC R

Freedman et al. (2013)

A

Cyr et al. (2011)

Coulson et al. (2010)

M

Clinical factors

Chan and McGregor (2012)

Byfield et al. (2016)

Boons et al. (2016)

Barron et al. (2009)

Adusumilli et al. (2017)

Table 2 Summary of factors associated with uptake of targeted trastuzumab therapy

✓

~ ✓

~

~

~

✓✓

~ ~

~

~

~ ✓

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~

~

M

Socioeconomic status Income

~

N U SC R

Psychosocial factors Patient refused therapy Clinician withheld therapy and no reason given/not indicated Sociodemographi c factors Education

~

~ ~

~ ✓✓

Insurance status

✓

~

~

✓✓

~

~ ~

PT

Ethnicity

ED

Marital status

Geographical region (urban/rural, SEER region) Institution

~

~

Employment

Age

✓✓

~

~

✓

~

✓

~

~

~ ~

✓

✓

✓

✓

✓

✓✓ ✓✓ ~

✓ ~

~

~

~

✓✓

~

~

~

~

✓

~

✓✓

A

CC E

Notes: ~, tested, but not statistically significant; ✓, tested in univariable analyses, and significant; ✓✓, tested multivariable, and significant.

Page 42 of 44

I N U SC R Total events (ref)

Heterogeneity

Summary unadjusted odds ratio M-H, Random, 95% CI

A

Table 3 Summary of meta-analysis of factors associated with initiation of trastuzumab therapy

1834/2328 652/796

747/1283 1929/2815

P=0.0002, I2=76% P=0.03, I2=54%

3.55 (2.415.23)**** 2.07 (1.442.96)***

1920/3274 1874/2754

184/425 1018/1873

P=0.008, I2=63% P=<0.00001, I2=81%

2.55 (1.534.25)** 1.74 (1.232.47)*

559/940 1297/1844 794/1133

108/341 1096/2018 2500/2601

P=0.41, I2=0% P=0.79, I2=0% P=0.88, I2=0%

3.16 (2.434.11)**** 2.02 (1.762.32)**** 1.80 (1.542.10)****

38–40,42,43,46,47

1072/1514

1218/2221

P<0.00001, I2=90%

1.63 (0.952.80)

25,30,38,40,42,43,46–48

1227/1733 213/374 103/147

2068/3345 231/337 71/95

P=0.74, I2=0% P=0.32, I2=14% P=0.99, I2=0%

1.54 (1.351.77)**** 1.05 (0.741.50) 0.79 (0.441.42)

1802/2611 2094/3205

595/1127 193/407

P=0.22, I2=29% P=0.55, I2=0%

1.62 (1.321.99)**** 1.52 (1.221.88)***

1558/1926 2710/3398 3409/4235

2413/3525 978/1534 485/1034

P=0.002, I2=68% P=0.002, I2=72% P<0.00001, I2=81%

2.15 (1.582.92)**** 2.59 (1.883.56)**** 3.90 (2.536.03)****

Total events

Studies included

Tumour stage: ≥Stage II vs. stage I (ref) ≥Stage III vs. stage I-II (ref)

24,25,30,33,38,46–48

Tumour grade: ≥Grade 2 vs. grade 1 (ref) ≥Grade 3 vs. ≤grade 2 (ref)

38–40,42,43,46–48

A

Hormone receptor status: HR positive vs. negative (ref) ER positive vs. negative (ref) PR positive vs. negative (ref)

Comorbidity (CCI): CCI 0 vs. >0 (ref) CCI ≤1 vs. >1 (ref)

Age: <50 vs. ≥50 (ref) <60 vs. ≥60 (ref) <70 vs. ≥70 (ref)

M

ED

48,54

CC E

Lymph node status: Positive vs. negative

30,38,40,43,46–48,58

39,40,42–44,46,47

PT

Tumour size: ≥1cm vs. <1cm (ref) ≥2cm vs. <2cm (ref) ≥3cm vs. <3cm (ref)

24,25,30,33,38,46–48

40,42–44,46,47

24,25,33,39,40 25,40

30,33,38,42,43,47 30,33,42,43,47

30,33,38,40,41,43,46,54 30,38,40,41,43,46,54

30,38,41,47,51,54

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I N U SC R

Ethnicity: White vs. black (ref) White vs. other (ref) White vs. non-white (ref)

296/440 421/575 717/1015

P=0.15, I2=38% P=0.57, I2=0% P=0.11, I2=44%

1.26 (0.921.72) 0.82 (0.661.01) 0.99 (0.791.24)

802/1183

P=0.82, I2=0%

1.13 (0.941.36)

1121/1795

1650/2499

P=0.14, I2=43%

1.03 (0.861.25)

30,38,42,46,47,52

2870/4205 2200/3412 2870/4205

30,38,42,46,47

A

38,42,46,47,52

Education: High vs. low (ref)

30,46,47

Socioeconomic status: High vs. low (ref)

30,33,42,46,47

Marital status: Married vs. single (ref)

42,46,47

694/1276

1078/1766

P=0.17, I2=44%

0.84 (0.681.04)

Geographical region: Rural vs. urban (ref)

46,47,54

461/798

1798/2433

P=0.90, I2=0%

0.83 (0.611.12)

ED

M

996/1349

A

CC E

PT

Test for overall effect: **** = P<0.00001, ***=P<0.0001, **=P<0.001, *=P<0.01; Ref = Reference.

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